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Abstract

Calcium-independent noradrenaline release was studied in the isolated perfused rat heart under conditions of normoxia, cyanide intoxication, and ischemia. The release of endogenous noradrenaline and dihydroxyphenylglycol were determined by high-performance liquid chromatography. The release of dihydroxyphenylglycol, the main neuronal noradrenaline metabolite, was used as an indicator of the free axoplasmic amine concentration. When storage function of neuronal vesicles was disturbed by Ro 4-1284 or trimethyltin, high dihydroxyphenylglycol release was observed without concomitant overflow of noradrenaline. If, however, these agents were combined with inhibition of Na+K+-ATPase or with veratridine-induced entry of sodium into the neuron, both dihydroxyphenylglycol and noradrenaline were released. Noradrenaline release was independent of extracellular calcium and was suppressed by blockade of neuronal catecholamine uptake (uptake1), indicating nonexocytotic noradrenaline liberation from the sympathetic nerve ending. This release critically depended on two conditions: 1) increased cytoplasmic concentrations of noradrenaline within the sympathetic neuron and 2) intraneuronal sodium accumulation. Both conditions together were required to induce noradrenaline efflux across the plasma membrane using the uptake1 carrier in reverse of its normal transport direction. A disturbed energy status of the sympathetic neuron, induced by cyanide intoxication or ischemia, likewise caused calcium-independent noradrenaline release by interfering with both vesicular storage function and neuronal sodium homoeostatis. Again, release was sensitive to uptake1 blockade. Since neuronal sodium accumulation was the rate-limiting step, release was further accelerated when residual Na+,K+-ATPase activity was inhibited. Na+-H+ exchange was identified as the predominant pathway of sodium entry into the sympathetic nerve ending in ischemia, and its inhibition by amiloride and ethylisopropylamiloride markedly suppressed ischemia-induced noradrenaline release.